Aminoalkoxy substituted benzodioxanes



United States Patent 3,124,598 AMINOALKOXY SUBSTITUTED BENZODIOXANES Lincoln Harvey Werner, Summit, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 8, 1962, Ser. No. 215,513 Claims. (Cl. 260-3403) The present invention concerns benz-etherified hydroxy-l,4-benzodioxanes. More particularly, it relates to benz-N-substituted amino-lower alkyl-oxy-1,4-benzodioxanes, in which lower alkyl of the N-substituted amino-lower alkyl-oxy group attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus separates the N-substituted amino group from the oxy group by at least two carbon atoms, or salts of such compounds, as Well as process for the preparation thereof.

This application is a continuation-in-part of application S.N. 141,976, filed October 2, 1961, now abandoned.

An Nsubstituted amino-lower alkyl-oxy group attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus, is more particularly a group having the formula:

O(C,,I-I )1 IR1 in which R represents an aliphatic radical, a cycloaliphatic radical, a cycloaliphatic-aliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical or a heterocyclic aryl-aliphatic radical, R stands for hydrogen, an aliphtic radical, and when taken together with R for alkylene, oxa-alkylene, thia-alkylene or aza-alkylene, the letter It stands for an integer from two to seven, and the group of the formula -(C,,H separates the nitrogen atom from the oxygen atom by at least two carbon atoms.

An aliphatic radical representing the group R, has from one to ten carbon atoms, and represents primarily alkyl having from one to twelve carbon atoms, such as lower alkyl, having from one to seven, such as from one to four, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, as Well as n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, 2,2,3,3-tetramethyl-butyl, 5,5-dimethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like. It may also represent lower alkenyl having from two to twelve carbon atoms, preferably lower allylic alkenyl having from three to five carbon atoms, e.g. allyl, 2-methyl-allyl, Z-butenyl and the like, as well as undecenyl and the like, lower alkyrlyl, having from two to seven, preferably from three to five, carbon atoms, e.g. propargyl and the like, or any other suitable aliphatic radical.

A cycloaliphatic radical representing R has from three to eight ring carbon atoms, and is more especially cycloalkyl having from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyl, cyclohexyl, as well as cyclopropyl, cyclobutyl, cycloheptyl, cyclo-octyl and the like. It may also represent cycloalkenyl having from five to eight, preferably from five to six, ring carbon atoms, e.g. 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexeny1 and the like, as well as Z-cycloheptenyl, 3-cyclo-octenyl and the like, or any other suitable cycloaliphatic radical. These cycloaliphatic groups are unsubstituted, but may contain one or more than one of the same or diiferent substituents, particularly aliphatic groups, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, or any other suitable substituent.

In a cycloaliphatic-aliphatic radical, representing R the cycloaliphatic portion has the meaning given above and stands particularly for cycloalkyl having from three to eight, preferably from five to six, ring carbon atoms, as well as cycloalkenyl having from five to eight, preferably from five to six, ring carbon atoms. The aliphatic radical connecting such cycloaliphatic portion with the nitrogen atom, has from one to seven, preferably from one to four, carbon atoms, and stands primarily for lower alkylene having from one to four carbon atoms, which may be arranged in a straight or in a branched carbon chain, e.g. methylene, l,l-ethylene, 1,2-ethylene, 1-methyl-1,2-ethylene, 2-methyl-l,2-ethylene, 1,3-propylene, 1,3-butylene, 1,4-butylene, 2,3- butylene and the like. A cycloaliphatic-aliphatic radical may, therefore, be represented by cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight, preferably from five to six, carbon atoms, e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cycloheptylmethyl, cyclo octylmethyl, 1 cyclopentylethyl, 1 cyclohexylethyl, l-cycloheptylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, Z-cyclohexylethyl, 2-cycloheptylethyl, l-cyclopentylpropyl, 2-cyclopentylpropyl, 3-cyclopentylpropyl, 4-cyclopentylbutyl, l-cyclohexylpropyl, 2-cyclohexylpropyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl and the like, cycloalkenyl-lower alkyl, in which cycloalkenyl has from five to eight, preferably from five to six, ring carbon atoms, e.g. l-cyclopentenylmethyl, 2 cyclopentenylmethyl, '3 cyclopentenylmethyl, l-cyclohexenylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, l-cycloheptenylmethyl, 1-(2-cyclopentenyl)- ethyl, 1-(3-cyclopentenyl)-ethyl, l-( l-cyclohexenyl)-ethyl, 1-(2-cyclohexenyl)-ethyl, l-(3-cyclohexenyl)-ethyl, 2-(1- cyclopentenyl) ethyl, 2 (2-cyclopentenyl)-ethyl, 2-(3- cyclopentenyl)-ethyl, 2-(2-cyclohexenyl)-ethyl, 2-(3-cyclohexenyl) ethyl, 1 (cyclopentenyl) propyl, l (3- cyclopentenyl) propyl, 2 (Z-cyclopentenyl)-propyl, 2- (3-cyclopentenyl)-propy1, 3-(l-cyclopentenyl)-propyl, 4- (3-cyclopentenyl) -butyl, 1-(Z-cyclohexenyl)-propyl, 1- (3-cyclohexenyl -propyl, 2- 1-cyclohexenyl)-propyl, 3- (3-cyclohexenyl)-propyl, 4-(3-cyclohexenyl)-butyl and the like, cycloalkyl-lower alkenyl, in which cycloalkyl has from three to eight, preferably from five to six, ring carbon atoms, e.g. 3-cyclopentylallyl, 3-cyclohexylallyl, 4- cyclopentyl-Z-butenyl and the like, or cycloalkenyl-lower alkenyl, in which cycloalkenyl has from five to eight, preferably from five to six, ring carbon atoms, e.g. 3- 1-cyclopentenyl)-allyl, 3- (2-cyclohexenyl) -allyl, 4- 3- cyclohexenyD-Z-butenyl and the like, or any other cycloaliphatic-aliphatic radical.

A carbocyclic aryl radical representing R is primarily a monocyclic or a bicyclic carbocyclic aryl radical, eg. phenyl, l-naphthyl or 2-naphthyl, or phenyl, l-naphthyl or Z-naphthyl substituted by one or more than one of the same or different substituents, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy and the like, halogens, e.g. fluoro, chloro, bromo and the like, trifiuoromethyl or any other suitable substituent.

The carbocyclic aryl-aliphatic radical represent ng R is primarily a monocyclic or a bicyclic carbocyclic arylaliphatic radical, particularly phenyl-lower alkyl, in which lower alkyl is represented by lower alkylene having from one to three carbon atoms, e.g. methylene, 1,1-ethylene, 1,2-ethylene, 1-methyl-1,2-ethylene, 2-methyl-1,2-ethylene, or 1,3-propylene. A carbocyclic aryl-aliphatic radical is, therefore, represented by phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl, 3-phenylpropyl and the like, as well as naphthyl-lower alkyl, e.g. l-naphthyl-methyl, 2-(1-naphthyl)-ethyl, Z-naphthylmethyl, 1-(2-naphthyl)- ethyl and the like, or phenyl-lower alkyl and naphthyllower alkyl, in which phenyl and naphthyl are substituted by one or more than one of the same or difierent substituents, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy and the like, halogeno, e.g. fiuoro, chloro, bromo and the like, trifiuoromethyl or any other suitable substituent. A monocyclic or bicyclic carbocyclic arylaliphatic radical is also a phenyl-lower alkenyl or a naphthyl-lower alkenyl radical, e.g. Z-phenylallyl, 3-phenylallyl, 3-(1-naphthyl)-allyl, 3-(2-naphthyl)-allyl and the like, or phenyl-lower alkenyl and naphthyl-lower alkenyi, in which phenyl and naphthyl are substituted as shown before, or any other suitable carbocyclic aryl-aliphatic radical.

A heterocyclic aryl radical representing R is more especially a monocyclic heterocyclic aryl radical, particularly a monocyclic azacyclic aryl radical, for example, pyridyl, e.g, Z-pyridyl, 3-pyridyl or 4-pyridyl, or any other monocyclic heterocyclic, such as oxacyclic or thiacyclic, aryl radical, such as furyl, e.g. Z-furyl and the like, or thienyl, e.g. Z-thienyl and the like. These groups may be unsubstituted or substituted by one or more than one of the same or different substituents, such as lower alkyl, e.g. methyl, ethyl, n-propyl, ispropyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. chloro, bromo and the like, or any other suitable sub stituent.

A heterocyclic aryl-aliphatic radical representing R is particularly a monocyclic heterocyclic aryl-aliphatic group, such as a monocyclic azacyclic aryl-lower alkyl radical, for example, pyridyl-lower alkyl, e.g. Z-pyridylmethyl, 4-pyridylrnethyl, 2-(2-pyridyl)-ethyl and the like, a monocyclic oxacyclic aryl-lower alkyl radical, for example, furyl-lower alkyl, e.g. furfuryl and the like, a monocyclic thiacyclic aryl-lower alkyl-radical, for example, thienyl-lower alkyl, e.g. Z-thenyl and the like, or any other suitable heterocyclic aryl-aliphatic radical, for example, a monocyclic heterocyclic aryl-aliphatic radical, in which the monocyclic heterocyclic aryl group is substituted by one or more than one of the same or different substituents, such as lower alkyl, e.g. methyl, ethyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or any other suitable substituent.

The group R is hydrogen, but may also stand for an aliphatic radical, particularly alkyl, such as lower alkyl having from one to seven, preferably from one to four, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, nbutyl and the like, or any other suitable aliphatic radical, such as one of those mentioned before.

The groups R and R substituting the nitrogen atom of the amino group in the amino-lower alkoxy substituent,

may also be taken together and form an alkylene radical having from two to eight, preferably from four to seven carbon atoms, e.g, 1,4-butylene, 1,5-pentylene, l,6-heptyl ene, 1,7-heptylene and the like, an oxa-alkylene radical having preferably four carbon atoms, e.g. 3-oxa-l,5-penene and the like.

The alkyl group separating the nitrogen atom of the amino group and the oxygen atom by at least two carbon atoms is represented in the above formula by (C H in which the letter It stands for a whole number from two to seven, particularly from two or three, and which separates the oxygen atom from the nitrogen atom in the substituent of the formula by at least two, preferably by from two or three, carbon atoms. Such group is, therefore, lower alkylene having from two to seven, preferably from two to three, carbon atoms, and separating the oxygen atom and the nitrogen atom attached to it by at least two, preferably by from two to three carbon atoms; members of such alkylene radical are, for example, 1,2-ethylene, l-methyl-LZ-ethylene, 2-methyl-1,2-ethylene, or 1,3-propylene, as well as 1,3-butylene, 1,4-butylene, 1,4-pentylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene and the like.

The remainder-of the carbocyclic aryl portion of the 1,4-benzodioxane nucleus carrying the above amino-lower alkyl-oxy substituent, is preferably unsubstituted; however, it may contain, in addition to the amino-lower alkyloxy group, one or more than one of the same or different substituents attached to'any of the three positions available for substitution, such as aliphatic radicals, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, trifiuoromethyl, etherified hydroxyl, for example, lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, lower alkenyloxy, e.g. allyloxy and the like, phenyl-lower alkoxy, e.g. benzyloxy and the like, or any other etherified hydroxyl group, esterified hydroxyl, primarily halogeno (representing hydroxyl esterified by a hydrohalic acid), e.g. fluoro, chloro, bromo and the like, etherified mercapto, for example, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, for example, tertiary amino, particularly N,N,di-lower alkylamino, e.g. N,N-dimethylamino, N-ethyl-N-rnethyl-amino, N,N-diethylarnino and the like, or any other suitable substituent.

The 2-position and the 3-position of the 1,4-benzodioxane nucleus are preferably unsubstituted; however, each of these positions may carry one or two of the same or different groups. Suitable substituents are, for example, aliphatic radicals, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, lower alkenyl, e.g. allyl and the like, or any other suitable aliphatic radical, cycloaliphatic radicals, such as cycloalkyl having from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyl, cyclohexyl, as well as cyclopropyl, cycloheptyl and the like, or cycloalkenyl having from five to eight, preferably from five to six, ring carbon atoms, e.g. 2-cyclopentenyl, 3-cyclopentenyl, l-cyclohexenyl, 3-cyclohexenyl and the like, as well as 2-cycloheptenyl, 3-cyclo-octenyl and the like, or any other cycloaliphatic radical, cycloaliphatic-aliphatic radicals, particularly cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentylmethyl, l-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl and the like, or any other cycloaliphatic-aliphatic radical, carbocyclic aryl radicals, particularly monocyclic carbocyclic aryl, e.g. phenyl or phenyl substituted by one or more than one of the same or different substituents, such as lower alkyl, e.g. methyl, ethyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy, isopropyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, trifluoromethyl or any other suitable substituent, or carbocyclic aryl-aliphatic radicals, particularly monocyclic aryl-lower alkyl, such as phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like, or phenyl-lower alkyl, in which phenyl is substituted by one or more than one of the same or different substituents, such as lower alkyl, e.g. methyl, ethyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy, isopropyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, triiluoromethyl or any other suitable substituent.

Salts of the compounds of this invention are particularly pharmaceutically acceptable, non-toxic acid addition salts, for example, those with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or those with hydrogen, as well as for lower alkyl, the letter 11' is one of the integers 2. and 3, and the group of the formula (C,,'H. separates the oxygen atom from the nitrogen atom by two to three carbon atoms, and

pharmaceutically acceptable, non-toxic acid addition salts thereof.

This group of compounds may be represented by S-(N- alkyl-amino-lower alkyl-oxy)41,4-benzodioxanes, S-(N-cycloalkyl-amino-lower alkyl-oxy)-1,4-benzodioxanes, S-(N- cycloalkyl-lower alkyl-amino-lower alkyl-oXy)-1,4-benzodioxanes, S-(N-phenyl-lower alkyl-amino-lower alkyloxy)-1,4benzodioxanes, and 5-(N,N-di-lower alkyl-amino-lower alkyl-oxy)-1,4-benzodioxanes, in which lower alkyl of the amino-lower alkyl-oxy portion has from two to three carbon atoms and separates the amino group from the oxy group by two to three carbon atoms, and cycloalkyl has from five to six ring carbon atoms, and pharmaceutically acceptable, non-toxic acid addition salts thereof.

The new compounds of this invention may be used in the form of composition for external or parenteral administration, which contain the new compounds or the salts thereof in admixture with an organic or inorganic, solid or liquid carrier. For making up the preparations there are employed substances which do not react With the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols, petroleum jelly or any other known carrier used for parmaceutical preparations. They may be in solid form, for example, as tablets, dragees, capsules and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like, and, if desired, may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying, coloring, flavoring agents and the like, salts for varying the osmotic pressure, organic acids, such as organic carboxylic acids, e.g. formic, acetic, propionic, glyco-lic, malonic, succinic, maileic, hydroxy-maleic, fumaric, malic, tartaric, citric, ascorbic, benzoic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, 2-acetoxy-benzoic acid and the like, or organic sulfonic acids, e.g. methane su'lfonic, ethane sulfonic, Z-hydroxyethane sulfonic, ethane 1,2-disulfonic acid, benzene sulfonic, p-toluene sulfonic, naphthalene Q-sulfonic acid and the like.

The compounds of this invention have long-lasting antihypertensive properties and can, therefore, be used as antihypertensive agents, for example, in renal hypertension or similar hypertensive conditions. As compared with known antihypertensive drugs, which show some tranquilizing and sedative properties, the compounds of this invention are free from such effects; certain compounds of this invention even have stimulating properties.

A preferred group of compounds, which show strong and long-lasting antihypertensive properties may be represented by the formula:

i H-R in which R represents alkyl having from one to twelve carbon atoms, cycloalkyl having from five to six ring carbon atoms, cycloalkyl-lower alkyl, in which cycloalkyl has from five to six ring carbon atoms, and lower alkyl has from one to four carbon atoms, phenyl, phenyl-lower alkyl, in which lower alkyl has from one to four carbon atoms, pyridyl or pyridyldower alkyl, in which lower alkyl has from one to four carbon atoms, R is hydrogen or lower alkyl, each of the groups R, and R stands primarily for buffers, etc. They may also contain, in combination, other useful substances.

The compounds of this invention may be prepared according to known methods. I prefer to react an N-substituted amine, particularly an amine of the formula:

R2 H-I -R in which R and R have the previously-given meaning,

with a benz-X-lower alkyl-oxy-l,4-benzodioxane, in which X represents a reactive esterified hydroxyl group, and lower alkyl of the X-lower alkyl-oxy group attached to the carbocyclic aryl portion of the 1,4benzodioxane nucleus separates the group X from the oxy group by at least two carbon atoms, particularly a benz-X-lower kyl-oxy-1, 4-henzodioxane, in which X-lower alkyl-oxy attached to the carbocyclic aryl portion has the formula --O(C H )X, in which X, the group -(C 'H and the letter n have the previously given meaning, and, if desired, converting a resulting salt into a free compound or into another salts, and/ or, converting a free compound into a salt thereof.

A reactive esterified hydroxyl group X is particularly a hydroxyl group esterified with a strong inorganic acid,- such as a mineral acid, particularly a hydrohalic acid, e.g. hydrochloric, hydrobromic, hydriodic acid and the like, as well \as sulfuric acid and the like, or a strong organic acid, such as a monocyclic carbocyclic aryl sulfonic acid, e.g. p-toluene sulfonic acid and the like, or a lower alkane sulfonic acid, e.g. methane sulfonic acid, ethane sulfonic acid and the like. The group X in the above formula is, therefore, primarily represented by halogeno having preferably an atomic weight greater than 19, such as chloro, bromo or iodo, as well as an organic sulfonyloxy group, such as monocyclic carboxylic sulfonyloxy, e.g. 4-methyl-phenyl-sulfonyloxy and the like, or lower alkyl sul fonyloxy, e.g. methyl sulfonyloxy, ethyl sulfonyloxy and the like.

The reaction is preferably carried out by treating the amine with the benz-X-lower alkyl-oxy-1,4-benzodioxane compound while maintaining an excess of the amine in the reaction mixture. Alcohols, such as lower alkanols, e.g. methanol, ethanol and the like, or any other suitable diluent may be used as solvents. If necessary, an alkaline reagent, such 'as an alkali metal carbonate, e.g. sodium carbonate, potassium carbonate and the like, or an organic base, e.g. pyridine and the like, may be used to neutralize any generated acid. The reaction is preferably performed at an elevated temperature, if necessary, in a closed vessel and/ or in the atmosphere of an inert gas, e.g. nitrogen.

The starting materials used in the above reaction may be prepared according to known methods; for example, a benz-hydroxy-1,4-benz0dioxane or a salt, such as a metal, e.g. alkali metal, salt thereof, may be reacted with an X-lower alkyl halide, in which X has the previouslygiven meaning, with the proviso that whenever X stands for halogeno, the halide atom has the higher molecular weight than X, and lower alkyl separates X from the halide atom by at least two carbon atoms, or with a hydroxy-lower alkyl-halide, in which lower alkyl separates the hydroxyl group from the halide atom by at least two carbon atoms, preferably in the presence of a suitable base, such as an alkali metal hydroxide, e.g. sodium hydroxide and the like, and in a resulting compound having a hydroxyl group, such hydroxyl group is converted into a reactive esterified hydroxyl group according to known methods, for example, treatment with a thionyl halide, e.g. thionyl chloride and the like, or an organic sulfonic acid halide, e.g. p-toluene sulfonic acid chloride and the like, the acid chloride preferably in the presence of a base, e.g. pyridine and the like.

The starting materials are new and are intended to be included within the scope of this invention. The X-lower alkyloxy substituent in a benz-X-lower alkyl-oxy-1,4-benzodioxane compound may be represented by the formula -O(C H )--X, in which X and the letter n have the previously-given meaning. Particularly useful as intermediates are the compounds of the formula:

in which R,,, R and the letter n have the previouslygiven meaning, and Hal stands for halogeno, preferably having an atomic weight greater than 19, especially chloro, as well as bromo or iodo.

Benz-N-substituted amino-lower alkyl-oxy-l,4-benzodioxane compounds of this invention, in which amino is substituted by an aliphatic, a cycloaliphatic, a cycloaliphatic-aliphatic, a carboc clic aryl-aliphatic or a heterocyclic aryl-aliphatic radical, in which amino-lower alkyloxy attached to the carbocyclic aryl portion of the 1,4- benzodioxane nucleus has the formula:

in which R is an aliphatic, a cycloaliphatic, a cycloaliphatic-aliphatic, a carbocyclic aryl-aliphatic or a heterocyclic aryl-aliphatic radical described hereinbefore, and R and the letter 11 have the previously-given meaning, may be prepared by reacting a benzamino-lower alkyl-oxy-1,4- benzodioxane compound, in which the amino group carries at least one hydrogen atom and is separated from the oxygen atom by at least two carbon atoms, particularly a compound, in which amino-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula O(C l-I )-NHR in which R and the letter 11 have the previously-given meaning, with a reactive ester of an aliphatic, a cycloaliphatic, a cycloaliphatic-aliphatic, a carbocyclic aryl-aliphatic or a heterocyclic aryl-aliphatic alcohol, particularly a reactive ester having the formula R X, in which X has the previously-given meaning, and R stands for one of the abovementioned groups, and, if desired, carrying out the optional steps.

The above reaction is carried out as previously-shown; the starting materials are prepared according to known methods, such as the previously-described procedure used for the preparation of benz-N-substituted amino-lower alkyl-oxy-l,4-benzodioxane compounds.

Benz-N-substituted amino-lower alkyl-oxy-1,4-benzo-dioxanes of this invention, in which the portion of the lower alkyl radical located adjacent to the amino group is methylene, particularly those, in which N- ubstituted aminolower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula:

in which R R and the letter n have the previously-given meaning, may also be prepared by converting the N-substituted carbamyl group in a benZ-N-substituted carbamyllower alkyl-oxy-l,4-benzo-dioxane compound, particularly in a compound, in which N-substituted carbamyl-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula:

in which R R and the letter n have the previously-given meaning, into an N-substituted aminomethyl group, and, if desired, carrying out the optional steps.

Conversion of the carbonyl portion of a carbamyl group into methylene is carried out according to known methods, particularly by treatment with a reducing reagent capable of converting the carbonyl portion of an amide grouping into methylene. Suitable reducing agents are especially alkali metal aluminum hydrides or alkaline earth metal aluminum hydrides, particularly lithium aluminum hydride, as well as sodium aluminum hydride, magnesium aluminum hydride and the like; if necessary, these reagents may be used in the presence of an activator, for example, aluminum chloride and the like. The reac tion is carried out in the presence of a suitable solvent, for example, an ether solvent, e.g. diethyl ether, tetrahydrofuran and the like, and, if desired, at an elevated temperature, for example, at the refluxing temperature of the solvent. The desired amino compound may also be obtained by electrolytically reducing the carbamyl compound on a suitable cathode, such as mercury, lead, nickel cathode and the like, using a proper anode and suitable catholyte and anolyte media, Conversion of the carbonyl portion in a carbamyl group into methylene may also be carried out by treatment with hydrogen in the presence of a suitable catalyst, e.g. certain copper catalysts and the like.

The starting materials used in the above reaction may be prepared according to procedures generally used for the preparation of such carbamyl compound, for example, by treating a benz-halogeno-carbonyl-lower alkyl-oxy-1,4- benzodioxane, especially a compound, in which halogeno-carbonyl-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus, has the formula -O-(C H )-COHal, in which Hal and the letter 11 have the previously-given meaning, with an amine, such as the amine of the formula:

in which R and R have the previously-given meaning, according to known methods.

Benz-N-substituted amino-lower alkyl-oxy-1,4-benzodioxanes of this invention, in which the portion of the lower alkyl radical located adjacent to the amino group is methylene, particularly those, in which N-substituted amino-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula:

in which R R and the letter n have the previously-given meaning, may also be prepared by converting the N-substituted thiocarbamyl group in a benz-N-substituted thiocarbamyl-lower alkyl-oxy-l,4-benzodioxane compound, particularly in a compound, in which N-substituted thio carbamyl-lower alkyl-oxy attached to the carbo-cyclic aryl portion of the 1,4-benzodioxane nucleus has the formula:

in which R R and the letter n have the previously-given meaning, into an N-substituted aminomethyl group, and, if desired, carrying out the optional steps.

The above conversion may be carried out according to known methods, for example, by treating the N-substituted thiocarbamyl compound in a suitable, preferably in an alcoholic, solvent, e.g. methanol, ethanol and the like, with freshly prepared Raney nickel, or electrolytically reducing it according to the procedure outlined above for the reduction of the amides.

The starting materials may be prepared according to known methods, for example, from the previously-described carbamyl compounds by treatment with suitable reagents, e.g. phosphorus pentasulfide and the like.

Benz-N-substituted amino-lower alkyl-oxy-l,4-benzodioxanes of this invention, in which the portion of the lower alkyl radical located adjacent to the amino group is methylene and the N-substituted amino group is monosubstituted, particularly those, in which amino-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula in which R and the letter n have the previously-given meaning, may also be prepared by converting the N-substituted iminomethyl group in a benz-N-substituted iminomethyl-lower alkyl-oxy-1,4-benzodioxane, particularly in a compound, in which N-substituted iminomethyl-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula:

in which R and the letter n have the previously-given meaning, into an N-substituted aminomethyl group, and, if desired, carrying out the optional steps.

The above conversion of an imino group is carried out according to reduction procedures used for the removal of a Schifl? base-type double bond. For example, such double bond may be removed by treatment with catalytically activated hydrogen. Catalysts containing a metal of the eighth group of the periodic system may be used in the presence of hydrogen; for example, palladium, e.g. palladium on charcoal and the like, represents a suitable metal catalyst. The reduction is carried out by treating a solution of the Schifi base, for example, in a lower alkanol, e.g. methanol, ethanol and the like, with hydrogen, if desired, at an increased pressure, in the presence of the catalyst.

Preferred reduction reagents are light metal hydrides, particularly the alkali metal borohydrides, e.g. lithium borohydride, sodium borohydride and the like, as well as alkali metal aluminum hydrides, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, or alkaline earth metal aluminum hydrides, e.g. magnesium aluminum hydride. Reduction with these reagents is preferably carried in solution, the solvents being chosen according to the reactivity of the reagent. For example, an alcohol, such as a lower alkanol, e.g. methanol, ethanol, isopropanol and the like, if desired, aqueous mixtures thereof, may be used with an alkali metal borohydride; an ether, e.g. diethylether, tetrahydrofurane or 1,4-dioxane, is used with an alkali metal aluminum hydride. If desired, the reaction may be promoted by the addition of catalytic amounts of an activator, for example, aluminum chloride. The reaction is performed at room temperature or preferably at an elevated temperature, for example, at the boiling temperature of the solvent, and, if desired, in the atmosphere of an inactive gas, e.g. nitrogen.

The Schitf base-type starting materials may be prepared according to methods known per se, for example, by reacting a benz-formyl-lower alkyl-oxy-1,4-benzodioxane compound, especially a compound, in which formyllower alkyl-oxy attached to the carbocyclic portion of the 1,4-benzodioxane nucleus has the formula in which the letter n has the previously-given meaning, with an N-monosubstituted amine, such as an amine of the formula H NR in which R has the previouslygiven meaning, if necessary, in the presence of a solvent, such as an alcohol, for example, a lower alkanol, e.g. methanol, ethanol and the like, and/or while cooling or at an elevated temperature.

Benz-N-substituted amino-lower alkyl-oxy-1,4-benzodioxane compound, in which the portion of the substituent of the N-substituted amino group located adjacent to the nitrogen atom is a --CH group, particularly compounds, in which N-substituted amino-lower alkyloxy attached to the carbocyclic aryl portion of the 1,4- benzodioxane nucleus has the formula:

R2 O(CnHzu)l l-OHzRX in which R and the letter n have the previously-given meaning, and R is hydrogen or stands for the same groups as R may also be prepared by converting the N-carbonyl-amino portion in a benz-N-acylamino-lower alkyl-oxy-l,4-benzodioxane compound, in which lower alkyl of the N-acylamino-lower alkyl-oxy group attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus separates the acylamino group from the oxy group by at least two carbon atoms, particularly in a compound, in which N-acylamino-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula:

in which R R and the letter. n have the previouslygiven meaning, into a methylamino group, and, if desired, carrying out the optional steps.

The above reaction may be carried out according to the previously-described methods; the starting materials are prepared according to known procedures.

Benz-N-substituted amino-lower alkyl-oxy-1,4-benzodioxane compounds, in which the portion of the substituent of the N-substituted amino group located adjacent to the nitrogen atom is a CH group, particularly compounds, in which N-substituted amino-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula:

R2 n 2n) Z y in which R and the letter 12 have the previously-given meaning, and R has the same meaning as R may also be prepared by converting the N-thiocarbonyl-amino portion in a benz-N-thioacylamino-lower alkyl-oxy-1,4- benzodioxane compound, in which lower alkyl of the N-thioacylarnino-lower alkyl-oxy substituent attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus, separates the N-thioacylamino group from the oxy group by at least two carbon atoms, particularly in a compound, in which N-thioacylamino-lower alkyloxy attached to the carbocyclic aryl portion of the 1,4- benzodioxane nucleus has the formula:

R2 'O(CnHin) N CS Ry in which R R and the letter n have the previouslygiven meaning, into a methylamino group, and, if desired, carrying out the optional steps.

The above reaction may be carried out according to the previously-described methods; the starting materials are prepared according to known procedures.

Benz-'N-substi'tuted amino-lower alkyl-oxy-1,4benzodioxane, in which the portion of the substituent of the N- substituted amino group located adjacent to the nitrogen atom is a CI-I group, and the N-substituted amino group is monosubstituted, particularly compounds, in which amino-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula O-(C I-I )NH-CH -R in which R and the letter 11- have the previously-given meaning, may also be prepared by converting the methyleneamino portion in a benz-methylene-substituted amino-lower alkyl-oxy-1,4- benzodioxane compound, in which lower alkyl of the methylene-substituted amino-lower alkyl-oxy group attached to the carbocyclic aryl portion of the l,4-benzodi oxane nucleus separates the amino group from the oxy group by at least two carbon atoms, particularly in a compound, in which methylene-substituted amino-lower alkyl-oxy attached to the carbocyclic aryl portion of the 1,4-benzodioxane nucleus has the formula in which R and the letter n have the previously-given meaning, into a methylamino group, and, if desired, carrying out the optional steps.

The above reaction is carried out according to the previously-described methods; the starting materials are prepared according to known procedures.

Depending on the conditions used in the new compounds of this invention may be obtained in the form of the free bases or as the salts thereof. A salt may be converted into the free base in the customary way, for example, by reaction with an alkaline reagent, such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate, eg. sodium or potassium carbonate or hydrogen carbonate and the like, ammonia and the like, or with an anion exchange resin. A free base may be converted into an acid addition salt by reacting it or a solution thereof in a suitable solvent or solvent mixture with the appropriate inorganic or organic acid, such as one of those outlined hereinabove, or a solution thereof and isolating the desired salt. Salts may also be converted into other salts directly, for example, by treating the former with a metal, e.g. sodium, barium, silver and the like, salt of an acid, e.g. hydrochloric, maleic acid and the like, in a suitable solvent, or with an anion exchange preparation.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A mixture of 4.5 g. of -(2-chloroethyloxy)-1,4-benzodioxane and 6.14 g. of n-butylamine in 30 ml. of ethanol is heated for four hours to 150. The reaction mixture is concentrated under reduced pressure, the residue is taken up in diethyl ether, the organic solution is washed with water, separated and dried. Anhydrous hydrogen chloride is passed through the solution, the desired S-[Z-(N-nbutyl-amino) -ethyloxy]-1,4 benzodioxane hydrochloride of the formula:

)CI-lg-OHgNH-C4Hs(n) .Hor precipitates and is purified by washing it with ethyl acetate and recrystallizing it from isopropanol, M.P. 153-156; yield: 3.2 g.

The starting material may be prepared as follows: A mixture of 28.0 g. of 3-methoxy-catechol (pyrogallol 1- methyl ether), 40.0 g. of 1,2-dibromo-ethane, 28.0 g. of finely powdered potassium carbonate, 0.5 g. of copper powder and ml. of glycerin is heated for eight hours to 190 under an atmosphere of nitrogen and While stirring. After cooling, water is added and the organic material is extracted with benzene. The benzene solution is washed with dilute aqueous sodium hydroxide and water, dried and concentrated, and the remaining residue is distilled under reduced pressure. The 5-methoxy-l,4-benzodioxane is collected at 9698/0.4 mm.; yield: 15.1 g.

A mixture of 15.0 g. of S-methoxy-1,4-benzodioxane and 90 ml. of 48 percent aqueous hydrobromic acid is heated slowly until the temperature of the distillate reaches 125. After cooling, the reaction mixture is poured into 400 ml. of water, the organic material is extracted twice with 200 ml. of diethyl ether, the organic solution is washed, dried and evaporated. The residue is distilled under reduced pressure to yield 5-hydroxy-l,4-benzodioxane, B.P. 9698/0.5 mm.; yield: 11.2 g.

A solution of 8.2 g. of S-hydroxy-l,4-benzodioxane in 25 ml. of ethanol is added to 2.16 g. of sodium hydroxide in 25 ml. of ethanol, followed by 11.6 g. of 1-b-rorno-2- chloro-ethane in 10 ml. of ethanol. The reaction mixture is refluxed for 17 hours, then cooled and filtered to remove the sodium bromide. The filtrate is concentrated under reduced pressure, the residue is taken up in diethyl ether, the insoluble material is filtered off, and the filtrate i2 is evaporated to dryness. The oily residue crystallizes to yield 9.4 g. of 5-(2-chloroethyloxy)-1,4-benzodioxane of the formula:

which melts at 6973.

Example 2 Example 3 To 6.75 g. of 5-(2-chloroethyloxy)-l,4-benzodioxane in 40 ml. of ethanol is added a solution 5.4 g. of N,N- dimethylamine in ethanol; the mixture is heated in a sealed tube to for four hours and is then concentrated under reduced pressure. The residue is taken up in water, the organic material is extracted with diethyl ether, and the organic layer is separated and evaporated to dryness. The residue is dissolved in ethyl acetate and treated with a concentrated solution of hydrogen chloride in ethyl acetate. On cooling, the 5-[2-N,N-dimethyl-amino)-ethyloxy] 1,4-benzodioxane hydrochloride of the formula:

precipitates and is purified by treating it with ethyl acetate, MP. 71-73 Example 4 A mixture of 6.75 g. of 5-(2-chloroethyloxy)-1,4-benzodioxane in 40 ml. of ethanol and a solution of 7.9 g. n-octylamine in ethanol is heated in a sealed tube for four hours and then evaporated. The residue is partitioned between water and diethyl ether; the organic layer is diluted with a concentrated solution of hydrogen chloride in ethyl acetate, whereupon the 5-[2-(N-n-octylamino)-ethyloxy]-l,4-benzodioxane hydrochloride of the formula:

precipitates and is recrystallized from a mixture of isopropanol and diethyl ether.

Other compounds, which may be prepared according to the procedure of this invention are, for example, 5- [3 N-cyclohexyl-amino -propyloxy] -l ,4-benzodioxane,

13 [2-( N-cyclopentyl-N-methyl-amino) -ethyloxy] -l ,4-

benzodioxane, 5- [Z-(N-benZyI-amino) -ethyl-oxy] -l ,4-benzodioxane, 5- [2- (N-Z-phenylethyl-amino) -ethy1oxy] -1 ,4-benzodioxane, 5- [2-(N-cyclohexylmethyl-amino) -ethyloxy] -1,4-benzodioxane, 5- [2- (N-3 -cyclopentylpropyl-amino) -ethyloxy] -2,3 -dimethyl-1,4-benzodioxane, 5- [3 (N-Z-cyclopentylethyl-amino) -propyloxy] -1,4-benzodioxane, 5 [2-(N-2-cycloheptylethylamino) -2-methyl-ethyloxy] 1,4-benzodioxane, 5-{2-[N-(2-pyridylmethyl) -amino] -ethyloxy}-1,4-benzodioxane, 6- [2- (Z-phenylethyl) -aminoethyloxy] -l ,4-benzodioxane, 8-chloro-5-{2- [2- (3 ,4-dimethoxy-phenyl) ethyl] -amino ethyloxy}-1,4-benzodioxane, 5- 2-(4-chloro-benzyl -aminoethyloxy] -2,3 -dimethyl- 1,4-benzodioxane, 8-methyl-5- [2-N-( l-phenylethyl) -N-methyl-aminoethyl oxy] -l ,4-benzodioxane, 5- [2-( 1-piperidino)-ethyloxy]-1,4-benzodioxane, 5- 3 (4-morpholino -propyloxy] -1,4-benzodioxane, 5-[2-(4-methyl-1-piperazino)-ethyloxy] 1,4 benzodioxane and the like.

What is claimed is:

1. 5 (N alkyl amino lower alkyl-oxy)-1,4-benzodioxane, in which alkyl has from one to twleve carbon atoms, and lower alkyl separates the amino group from the oxy group by from two to three carbons atoms.

2. S-[Z-(N-n-butyl-amino)-ethyloxy] 1,4 benzodioxane.

3. S-[Z-(N-n-octyl-amino)-ethyloxy] 1,4- benzodioxane.

4. S-(N-cycloalkyl-lower alkyl-amino-lower alkyl-oxy)- 1,4-benzodioxane, in which lower alkyl separates the amino group from the oxy group by from two to three carbon atoms, and cyclo-alkyl has from five to six ring carbon atoms.

5. 5-[2-(2-cyclophentylethylamino) ethyloxy] 1,4- benzodioxane.

6. 5-(N,N-di-lower alkyl-amino-lower alkyl-oxy)-1,4- benzodioxane, in which lower alkyl separates the N-N- di-lower alkyl amino group from the oxy group by from two to three carbon atoms.

7. S-[2-(N,N-dimethyl-amino) ethyloxy] 1,4-benzodioxaue.

8. A compound of the formula:

in which each of the groups R and R stands for a member selected from the group consisting of hydrogen and lower alkyl, the letter n is an integer selected from the group consisting of 2 and 3, the group of the formula (C 'H separates the oxygen atom from the nitrogen atom by two to three carbon atoms, and Hal is halogeno having an atomic weight greater than 19.

9. 5 2-chloro-ethyloxy) l ,4-benzodioxane. 10. A member selected from the group consisting of a compound of the formula:

CH R, 'JH-Rb 0/ in which R is a member selected from the group consisting of alkyl having from one to twelve carbon atoms, cycloalkyl having from three to eight carbon atoms, cycloalkyl-lower alkyl, in which cycloalkyl has from three to eight carbon atoms, phenyl, phenyl-lower alkyl, [(lower alkyl)-phenyl]-lower alkyl [(lower alkoxy)- phenyl] -lower alkyl, [(halogeno)-phenyl]-lower alkyl, [(trifluoromethyl) -phenyl] -lower alkyl, and pyridyl lower alkyl, R is a member selected from the group consisting of hydrogen and lower alkyl, and when taken together with R alkylene having from four to seven carbon atoms, 3-oxa-1,5-pentylene, and 3-lower alky1-3-aza- 1,5-pentylene, the group of the formula (C H in which the letter it stands for an integer from 2 to 7, separates the oxygen atom from the nitrogen atom by at least two carbon atoms, each of the groups R and R is a member selected from the group consisting of hydrogen, and lower alkyl, and R is a member selected from the group consisting of hydrogen, lower alkyl and halogeno, and a pharmaceutically acceptable non-toxic acid addition salt thereof.

No references cited. 

2. 5-(2-(N-N-BUTYL-AMINO)-ETHYLOXY)-1,4-BENZODIOXANE.
 10. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 